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Full Text AI-92-10
PEDIATRIC AIDS CLINICAL TRIALS PROGRAM
NIH GUIDE, Volume 21, Number 39, October 30, 1992
RFA: AI-92-10
P.T. 34, AA
Keywords:
AIDS
Children (Patients)
Clinical Trial
National Institute Of Allergy And Infectious Diseases
Letter of Intent Receipt Date: November 13, 1992
Preapplication Meeting Date: December 7, 1992
Application Receipt Date: January 21, 1993
PURPOSE
The purpose of this Request for Applications (RFA) is to recompete
the Pediatric AIDS Clinical Trials Program in order to further
stimulate pediatric AIDS research. This program, initiated in 1988,
is supported by the Division of AIDS (DAIDS) of the National
Institute of Allergy and Infectious Diseases (NIAID). The Program is
designed to provide a distinct scientific emphasis on HIV disease in
children and a focus for addressing therapeutic research issues
related to this population.
The RFA calls for an emphasis on the development and evaluation of
pediatric therapeutic research in three major areas, namely: (1)
interruption of perinatal transmission of HIV, (2) antiretroviral
therapy, and (3) therapy and prophylaxis against opportunistic
infection in HIV disease. The target populations include: infants (0
to 12 months of age), children (13 months to 12 years of age), and
adolescents (13 through 18 years of age).
HEALTHY PEOPLE 2000
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of Healthy People 2000, a
PHS-led national activity for setting priority areas. This RFA,
Pediatric AIDS Clinical Trial Program, is related to the priority
area of HIV infection. Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report: Stock No 017-001-00474-0) or
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic, profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of state and local governments, and
eligible agencies of the Federal government. Applications from
minority individuals and women are encouraged. Existing pediatric
AIDS Clinical Trial Units (ACTUs), pediatric components of adult
ACTUs, as well as new applicants are invited to apply.
MECHANISM OF SUPPORT
Awards funded under this RFA will be supported through National
Institutes of Health (NIH) Cooperative Agreements (U01). Assistance
provided through the cooperative agreement differs from the
traditional research grant in that the Government component (NIAID)
anticipates substantial programmatic involvement during the
performance of the award. The nature of staff participation is
described under, Special Requirements: Terms and Conditions for
Award. All policies and requirements that govern the grants programs
of the PHS and the NIH apply to these cooperative agreements.
This RFA is a one-time solicitation with a specified deadline for
receipt of applications. Reissuance of this initiative is uncertain.
If by the end of the third year of award the NIAID has not announced
an intention to reissue the RFA, awardees who plan to apply for
continuing support should contact NIAID program officials for advice
on how to recompete.
FUNDS AVAILABLE
Approximately $23,000,000, total costs, will be available for the
first year funding. This level of support is dependent on the
receipt of a sufficient number of applications of high scientific
merit and availability of funds. Approximately 10-14 pediatric ACTUs
will be funded under this RFA. Awards will be made for a total
project period of four years. The anticipated earliest award date is
September 1, 1993.
Funding beyond the first and subsequent years of the award will be
contingent upon satisfactory performance during the preceding years,
including meeting research objectives and patient accrual targets,
and the continuing availability of funds for this purpose.
RESEARCH OBJECTIVES
The Pediatric AIDS Clinical Trials Program is a component of the
NIAID-supported AIDS Clinical Trials Group (ACTG). The ACTG is
composed of the AIDS Clinical Trials Units (ACTUs), the Statistical
and Data Analysis Center (SDAC), and the DAIDS Treatment and Clinical
Research Programs (See Appendix I, "Structure and Functions of the
ACTG"). In addition, further information about the ACTG is contained
in the Operations Manual ["Organization, Policies, and Procedures of
the AIDS Clinical Trials Group" (ACTG)], which is available by
calling Ms. Kym Adams in the ACTG Operations Office at (301)
230-3150.
The Pediatric AIDS Clinical Trials Program consists of NIAID-funded
Pediatric ACTUs, Pediatric components of Adult ACTUs, and pediatric
units supported by the National Institute of Child Health and Human
Development (NICHD) which participate in ACTG research. Appendix II
contains a listing of all the clinical trials sites of this program.
The primary research objectives of this Program are to evaluate the
pharmacokinetics, safety, tolerance, and efficacy of agents in order
to:
o reduce the rate of perinatal transmission of HIV;
o develop effective antiretroviral treatment of primary HIV
infection; and
o develop effective treatment and prophylaxis of opportunistic
infections (OIs).
These research aims will be addressed through a multi-center clinical
trials network in which Principal Investigators (PI) work
collectively (as a group) and cooperatively with NIAID staff to
devise and implement the most appropriate studies for these
objectives.
Special Requirements Terms And Conditions Of Award
o Terms and Conditions of Award
o Awardee Rights and Responsibilities
o Awardees must conduct clinical trials that focus on the three
research areas list above. At least 25 new patients per year must be
accrued onto pediatric protocols. The majority of the pediatric
protocols include patients to ages 17 or 18. Included may be
individuals classified as adolescents. Perinatal studies are unique
in the multi-disciplinary involvement and cooperation required for
their conduct. For these studies, awardees must provide coordinated
obstetrical research, care, and outreach. Most current and future
pediatric research protocols require multiple neurodevelopmental
tests. Thus awardees must also perform neuropsychological and
neurological testing as clinical endpoints of required studies.
o In addition to the 25 patients mentioned above, awardees who have
a particular interest in unique aspects of research on adolescents
will implement specific studies designed to focus on this population.
Institutions with a special interest in neurological and
neuropsychological testing will conduct studies of new and efficient
methods that could be used as measures of effectiveness in clinical
trials of antivirals.
o Pediatric ACTU investigators will be responsible for the overall
conduct of the research including developing concept sheets for
studies, protocol development, the accrual and retention of study
patients, production of high quality data, and the timely
dissemination of the research results.
o ACTU performance in each budget period will determine the base
budget award, release of increments of the base budget, and the
amount of incentive funding awarded during that budget period.
Accordingly, the PI will submit interim progress reports, due at the
end of five months after the beginning of the budget period. The
NIAID will provide information thatwhich includes accrual data, site
monitoring site visit reports and other performance factors for each
ACTU. Awardee institutions will be asked to provide budgetary
expenditures for the period of performance and a brief summary of
clinical research to date. The level of support in future award
years will be contingent upon performance. Inadequately justified
performance, such as not meeting minimum accrual goals without
justification or poor quality of data during a budget period may
result in reduction of future year awards or withholding of support.
o The PI and other key pediatric ACTU personnel will be required to
attend regularly scheduled ACTG meetings in the Washington, DC area
(or at a site designated by NIAID). The meetings will occur
approximately three times per year. Awardees must be willing to
participate in these activities and are expected to include such
plans in their budget requests.
o Investigators may form a Pediatric clinical trial unit through
consortium arrangements with other institutions or health care
agencies. They will be designated as subunits. The goals of such
arrangements are to: (1) to contribute substantially to the
capability of the awardee institution for providing the necessary
ancillary support services, including outreach, for recruiting and
retaining pediatric patients on clinical trials; (2) provide access
to patient populations (e.g., infants and children of minority and
substance abusing women, disenfranchised youth) not well represented
at the Main Unit; and (3) provide special clinical or scientific
expertise not available at the Main Unit. Ultimate financial and
scientific responsibility for subunits would reside with the main
unit of the ACTU.
o National Institute of Allergy and Infectious Diseases Rights,
Responsibilities, and Authorities
The role of NIAID staff will be to facilitate and not to direct ACTG
activities. The terms described in this section are in addition to,
and not in lieu of, otherwise applicable OMB administrative
guidelines, HHS Grant Administration Regulations in 45 CFR Part 74,
and other HHS, PHS, and NIH grant administration policy statements.
o The following support can be anticipated from the Treatment
Research Operations Program (TROP) and the Clinical Research Program
(CRP), which share responsibility for administering the major portion
of NIAID-sponsored ACTG research.
o The Associate Directors of TROP and CRP, will assist the ACTG
Executive Committee in establishing the scientific priorities of the
ACTG.
o The Chief, Pediatric Medicine Branch, CRP will assist in pediatric
protocol development including assisting the Chief, Clinical Research
Management Branch, TROP with review of protocols and advice on
effectiveness and appropriate utilization of resources.
o The Chief, Clinical Research Management Branch, TROP, will assist
in promoting the timely implementation and completion of those
clinical trials designated as priority studies by the ACTG Executive
Committee and the NIAID, and provide technical advice and assistance.
o The Associate Director, TROP, as a member of the ACTG Executive
Committee, will facilitate the early termination of a protocol for
reasons such asinsufficient accrual, patient safety and noncompliance
with 45 CFR Part 46, inconclusive results, when it has been
determined that further accrual will not add information of
scientific value, when the emergence of new information makes the
study question less relevant, when program objectives have been met,
or when the limitations on the program budget require that ACTG funds
be re-directed to higher priority areas.
o The Associate Director, TROP, will coordinate activities among
other areas of NIH-sponsored research and assist in dissemination of
results of clinical trials to the scientific and medical communities.
o The Chief, Operations and Data Management Branch, TROP, will
assist in providing operational and data management support.
The NIAID will serve as the sponsor for Investigational New Drug
(IND) Applications required for conducting studies of new agents
under evaluation by the ACTG, provide updated information on the
safety and efficacy of investigational new agents supplied to ACTUs
under an IND Application sponsored by the NIAID (Note: NIAID will not
provide investigational agents or guarantee expenditure of NIAID
funds for a study after requesting termination of the study).
o The Chief, Pharmaceutical and Regulatory Affairs Branch, TROP,
will conduct on-site visits to monitor the conduct of studies
involving the use of investigational agents, compliance with
regulations for Institutional Review Board (IRB) approval and
informed consent (compliance with 45 CFR 46), accuracy of data
recording, completeness of reporting adverse drug reactions, and
quality control (including periodic audits for quality assurance,
investigational drug handling, and drug accountability).
o The Chief, Clinical Research Management Branch, TROP, will conduct
on-site visits to review progress of the research, and issues
concerning administrative, technical, and fiscal management.
Fiscal Management - Clinical base funding consists of those resources
required to maintain an infrastructure and ancillary services
sufficient to accrue a projected minimum number of new patients each
year. Clinical base funding includes costs for personnel,
supplies/equipment, patient care, laboratory support for protocol-
mandated assays, ancillary services, and administrative costs.
Clinical base funding to ACTUs will be administered in the following
manner: the majority of clinical base funding will be released at
the beginning of the budget year. At mid- period, the performance of
the unit will be assessed by NIAID staff, using accrual, quality of
data, and other measures of performance. This assessment will be
based on an Interim Progress Report submitted by the PI. If unit
performance is satisfactory, the remaining increment of funding will
be released. In the event of unsatisfactory ACTU performance (e.g.,
failure to meet accrual goals, poor data quality etc.), the remaining
funds will be reduced or withheld. Continued inadequately justified,
poor performance during the remaining months of the budget period may
result in reduction of clinical core funding for the following budget
period or interruption of support.
The NIAID may set aside a portion of the total ACTG budget each year
for Incentive Funding. These funds will be used to support
activities such as: (1) funding of NIAID/ACTG designated high
priority protocols not anticipated at the beginning of the budget
period; (2) increasing focus on a scientific area during a budget
year for which resource needs exceed the funding of the individual
ACTUs; (3) funding to supplement costs incurred as a result of
substantial uncompensated participation by investigators in ACTG
activities (e.g., travel or other program work, such as a chair of an
ACTG scientific committee).
o For activities described herein that require approval by NIAID
staff during performance of this cooperative agreement (e.g.,
protocol review and approval, early termination of a protocol,
reports intended for inclusion in IND applications and clinical
brochures, distribution of investigational agents from the
government, etc.), the NIAID will establish an arbitration process to
resolve major differences of opinion. An arbitration panel, composed
of one pediatric ACTU designee, one NIAID designee, and a third
designee with expertise in the relevant area and chosen by the other
two will be formed to review any scientific or administrative issue
and to recommend an appropriate course of action to the Director,
DAIDS. In the event the NIAID is the holder of the IND, any action
taken by the NIAID under its responsibility for the safety of the
trial would not be subject to arbitration. The arbitration process
in no way affects the right of an award recipient to appeal an action
in accordance with PHS regulations in 42 CFR Part 50, Subpart D, and
HHS regulations in 45 CFR, Part 16.
o Cooperative Rights and Responsibilities
Shared rights and responsibilities of awardee institutions and the
NIAID can be summarized as follows
o ACTU - The scientific investigators at the ACTUs, through
scientific committees and the Executive Committee, with assistance
from TROP and CRP, develop a scientific agenda, set priorities for
clinical trials, and initiate the development of protocols. The
majority of ideas for clinical trials are initiated by ACTU
investigators. Most Phase III protocols are open to participation by
any ACTU. Phase I/Phase II protocols are usually conducted at a
limited number of ACTUs.
o Protocol Development - Ideas for individual studies may be
introduced from any source, although most come from ACTU
investigators. Proposed studies are summarized in the form of a
"concept sheet", which includes the study's rationale, objectives,
design, eligibility criteria, treatment regimen, sample size
estimates, and cost impact projections.
The concept sheets are reviewed by TROP and CRP staff members
comprising a Clinical Trials Review Committee (CTRC). The
appropriate Scientific Core Committees and the Executive Committee
review, approve, and prioritize concept sheets. Approved concept
sheets are developed into protocols by a team composed of a protocol
chair (an ACTU investigator); TROP and CRP representatives; an SDAC
statistician; an Operations Office representative; and immunologist,
virologist, pharmacologist, as required. Because most ACTG clinical
trials are conducted under an IND held by the DAIDS/NIAID, regulatory
requirements mandate review and approval of protocols by the NIAID
CTRC prior to their initiation. After FDA approval of the final
protocol it is opened for enrollment. Once a protocol has been
activated, the protocol chair is responsible for its ongoing
performance and is expected to take the lead in dissemination of
study results, including publication of results.
o ACTG meetings- Meetings of the entire ACTG are held up to three
times a year. The primary purpose of these meetings is to bring the
ACTG together to review the work of the scientific and resource
committees. This includes a review of the scientific agendas set
forth by the committees of the group, scientific plenary sessions
covering topics at the leading edge of HIV research, updates on
protocols, and workshops dealing with the conduct of ACTG studies and
operations. Invited guests from the FDA, the NIH, and pharmaceutical
industry also participate in these meetings as do representatives
from the Community Constituency Group (which includes HIV infected
persons) and other interested parties. The ACTG has a committee
structure consisting of scientific committees, resource committees,
and the Executive Committee.
The scientific committees form the scientific nucleus of the ACTG.
Each committee has a chair, vice chair, core member, and additional
members with relevant expertise and interest in the committee's
research area. Each committee has approximately 1-2 representatives
from TROP and CRP, 10-15 investigators, an HIV-infected person or
advocate, and a representative of the FDA.
The role of each Scientific Committee, together with TROP and CRP,
and the Executive Committee, is to develop a research agenda and
establish research priorities in a particular scientific area and
continually reassess those priorities relative to new research
opportunities; and to evaluate the conduct and status of active
studies.
In addition to providing general expertise, the Immunology, Virology,
and Pharmacology Committees also have responsibility for developing
and recommending laboratory quality assurance policies in the areas
of flow cytometry, viral assays, marker evaluation, and
pharmacological assays. The Committees meet during each ACTG meeting.
In addition, committees meet and/or are in contact at times other
than ACTG meetings.
Resource Committees were formed to provide technical expertise and
practical advice to the ACTG. There are three ACTG Resource
Committees: Site and Data Management, Patient Care, and the Community
Constituency Group.
The Executive Committee, in consultation with TROP and CRP, develops
general ACTG policies concerning committee structure and membership,
committee operations, publications, access to data, interim data
monitoring, and agendas for the group meetings. In addition, the
Executive Committee, with assistance from TROP and scientific
committees, and establishes scientific priorities for the ACTG. The
majority of the members of the Executive Committee are ACTU
investigators. Representatives from TROP and CRP, persons from the
Community Constituency Group (including HIV infected individuals),
and the SDAC also sit on the Executive Committee.
Access to Data, Ownership of Data, and Publication Policies
In addition to the reporting requirements currently in existence for
awardees of traditional NIH research project grants, the following
apply:
o Reports of data generated by the ACTG or any of its member
pediatric ACTUs that are required for the NIAID to fulfill its role
as sponsor of an investigational agent (data required for inclusion
in IND Applications, Clinical Brochures, and similar documents, as
well as periodic reports to the FDA and other regulatory agencies)
must be submitted by the PI upon request of the Chief, Pharmaceutical
and Regulatory Affairs Branch, TROP to the Operations Office. The
latter provides the services necessary to establish and maintain a
system for receipt and review of new concepts and systems to
coordinate activities related to implementation of ACTG studies.
o The NIAID will have access to all data generated under this
cooperative agreement and will periodically review the progress
reports. Information obtained from the data may be used by NIAID for
the preparation of internal reports on ACTG activities or safety
monitoring of protocols. However, the awardees will retain rights to
the data (see below). Publication of findings is the responsibility
of the investigators in accordance with the publication policies
established jointly by the ACTG investigators and the Associate
Director, TROP. Publication or oral presentation of work performed
under this agreement is the responsibility of the PI and will require
appropriate acknowledgement of NIAID support.
o ACTG member institutions will generate clinical trial data that
will be submitted to the Statistical Data and Analysis Center (SDAC).
In most cases, these institutional data will represent only a small
subset of the total database for a given clinical trial and
therefore, will have limited scientific value. The investigators,
with the assistance of the Associate Director, TROP, will establish
policies limiting publication of such institutional data. These
institutional data will remain the property of the awardee from which
they originated, even following submission to the SDAC.
o The entire database for a particular trial will usually come from
more than one institution. Although the data are physically located
at the SDAC, the use and publication of the data will be governed by
policies established by the ACTG investigators and the Associate
Director, TROP. The Associate Director, TROP, and the Associate
Director, CRP, will have access to the data and will require periodic
special reports of data generated by the ACTG or any of its members
as described above. However, publication or oral presentation is the
responsibility of the ACTG investigators, who must follow the
publication policies established by the ACTG.
o In the event of a collaboration with a pharmaceutical company for
the evaluation by the ACTG of an investigational agent, a memorandum
of understanding among the Associate Director, TROP, participating
pediatric ACTU Principal Investigators and the company will set forth
the details providing for access by the company to necessary data.
FAILURE TO ABIDE BY THESE TERMS OF AWARD MAY RESULT IN WITHHOLDING OF
FUNDS BY NIAID.
o STUDY POPULATIONS: SPECIAL INSTRUCTIONS FOR INCLUSION OF WOMEN
AND MINORITIES IN CLINICALRESEARCH POPULATIONS
NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
women in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them. This policy is
intended to apply to females of all ages. If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear compelling
rationale should be provided.
The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale
for its choice. In addition, gender and racial/ethnic issues should
be addressed in developing a research design and sample size
appropriate for the scientific objectives of the study. This
information should be included in the form PHS 398 in the Research
Plan and summarized in Item 5, Human Subjects.
Applicants/offerors are urged to assess carefully the feasibility of
including the broadest possible representation of minority groups.
However, NIH recognizes that it may not be feasible or appropriate in
all research projects to include representation of the full array of
U.S. racial/ethnic minority populations (i.e., Native Americans,
including American Indians or Alaskan Natives, Asian/Pacific
Islanders, African Americans, Hispanics/Latinos). The rationale for
studies on single minority population groups should be provided. For
the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.
The usual NIH policies concerning research on human subjects applies
to ACTUs and subunits. Basic research or clinical studies in which
human tissues cannot be identified or linked to individuals are
excluded. However, every effort should be made to include human
tissues from women and racial/ethnic minorities when it is important
to apply the results of the study broadly, and this should be
addressed by applicants.
If the required information is not contained within the application,
the application will be returned.
Peer reviewers will address specifically whether the research plan in
the application conforms to these policies. If the representation of
women and minorities in the study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.
All applications for clinical research submitted to NIH are required
to address these policies. NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.
STRUCTURE AND COMPOSITION OF THE APPLICATION
I. COMPONENTS OF THE RESEARCH PLAN FOR ACCRUAL OF AT LEAST 25
PATIENTS
Part A Pediatric Clinical Trials Unit (REQUIRED)
o Proficiency in Pediatric Clinical Trials
o Required Study Areas
o Optional Studies
o Administrative and Organizational Structure
o Facilities
o Outreach/Recruitment
o Ancillary Care/Linkages
o Data Management
o Pharmacy
o Immunophenotyping
Part B Laboratory Support
o Virology (REQUIRED)
o Immunology (OPTIONAL)
o Pharmacology (OPTIONAL)
Part C Developmental Research Component (ALL OPTIONAL)
o Virology
o Immunology
o Neuropsychological Assessment
PART A - PEDIATRIC CLINICAL TRIALS UNIT
IN PLACE OF ITEMS 1 - 4 OF THE RESEARCH PLAN (FORM 398), PLEASE
ADDRESS THE FOLLOWING AREAS:
o PROFICIENCY IN CONDUCT OF PEDIATRIC CLINICAL TRIALS (5 page limit)
Applicants are required to describe their clinical proficiency (past
performance) in the conduct of clinical trials.
o Describe the nature of previous pediatric clinical trials
experience. Applicants proposing optional studies (e.g., adolescent
or neuropsychological assessment studies) may elect to describe
proficiency in these areas under Section 3 below and only reference
those studies here.
o Describe the level of scientific participation in pediatric
clinical studies (e.g., protocol design, oversight, analysis of data,
etc). Current ACTG participants (hereafter called incumbents) should
include participation in Pediatric ACTU (or equivalent) activities
such as: chairing or participating on committees, chairing protocol
development/selection, submitting concept sheets, performing
laboratory tests and assays for collaborative efforts, and serving on
working groups. [For applications from incumbents, copies of
Institutional Evaluation reports will be provided to the reviewers.
Incumbents may describe circumstances or factors that might have
affected the site's performance and attainment of research
objectives].
o REQUIRED STUDY AREAS (5 page limit for each study area)
Applicants should describe a plan for clinical research in EACH of
the following areas: PERINATAL TRANSMISSION OF HIV, ANTIRETROVIRALS,
AND OIs.
o Describe the plan for participation in the three study areas as
indicated in the following table (e.g., antiretroviral studies should
focus on phases I/II/III, combination therapies and immune based
therapies, etc.). Using a table like the one below, provide an
estimate of how the total number of patients accrued in the first
year will be distributed among these studies.
Phase 1 Phase 2 Phase 3 Comb.
I. Based
Perinatal x x
Anti-HIV x x x x
x
x x
Total
o For each of these three areas (perinatal transmission,
antiretrovirals, opportunistic infections) the research plan should
describe the:
o nature of the proposed studies, including the conduct of
obstetrical research in the perinatal transmission studies;
o special scientific expertise of key investigators. The clinical
trials research capability and experience of each participating
obstetrician must be included in the perinatal studies;
o demographic features of potential study population;
o other unique features the proposed site might offer to the
pediatric ACTG effort; and
o nature, organization and relationship of the pediatric unit
vis-a-vis the obstetrical/prenatal care site which will provide care
to mothers and infants who will participate in perinatal studies.
Applicants must include a description of plans for the transition of
women from perinatal infection protocols into regular adult protocols
(e.g., linkages with an adult ACTU or HIV service within the same
institution, or with an adult ACTU or subunit in some other
institution).
o OPTIONAL STUDIES
o ADOLESCENTS (5 page limit)
Applicants having special expertise and interest in HIV INFECTION IN
ADOLESCENTS may submit plans describing their past proficiency and
proposed research for studies on this population. Adolescents
enrolled under this optional area may NOT be counted toward the 25
minimum number per year required for enrollment on pediatric
protocols.
PROFICIENCY
o Describe the nature of past experience in the conduct of clinical
trials research involving adolescent patients. The plan should
include:
o seropositivity rates, numbers of adolescent patients seen at
applicant institution, and the number of new adolescent patients
expected to be enrolled.
o arrangements to be implemented at patient care sites, half-way
homes, drug treatment centers, etc. to provide outreach to
HIV-infected adolescents in order to increase accrual (see
"Guidelines for Establishment of Subunits" in ppendix III). Letters
of agreement in support of subunit or other formal arrangements must
be included.
o Incumbents who received supplemental funding for adolescent
research in 1991 should present a summary of progress to date.
PROPOSED STUDY AREAS
Describe the types of clinical studies proposed for research on
adolescents.
o NEUROPSYCHOLOGICAL ASSESSMENT (5 page limit)
PROFICIENCY
Applicants having special expertise and interest in conducting
neuropsychological assessment and neurological testing may submit
plans for research in this area.
PROPOSED STUDY AREAS
Applicants should describe:
o any past experience in the conduct of neuropsychological and
neurological test batteries as measures of clinical endpoints;
o the types of studies proposed for research on pediatric patients
participating in ACTG studies. Include scientific expertise of each
investigator (neuropsychologist, neurodevelopmentalist, etc.).
o ADMINISTRATIVE AND ORGANIZATIONAL STRUCTURE (8 page limit)
Describe the administrative and organizational features that will be
implemented to support clinical studies in the required and optional
research areas. The description should address the following areas:
o organization - describe the proposed administrative and
organizational structure of the clinical trials unit; state whether
the clinical trials unit will be an integral part of the patient care
activities of the institution or constituted as a separate research
unit.
o personnel - describe the qualifications and responsibilities of
key administrative personnel.
Describe the type, number, qualifications and responsibilities of any
other personnel who might assist in the conduct of the studies, e.g.,
physicians or other health care personnel, and institution-supported
administrative personnel.
o FACILITIES (2 -3 page limit)
Describe the facilities available for performing ACTU studies and
delivering comprehensive care. The description should include
facilities for:
o outpatient and inpatient studies at the main pediatric ACTU and
any subunits; and
o patient care (e.g., where study subjects would receive care
primary health care, obstetrical, pediatric, etc.)
o OUTREACH/RECRUITMENT (5 page limit, plus supporting letters)
Provide a clear, concise plan for outreach to and recruitment of
pediatric patients, pregnant women, and adolescent patients, if
applicable. Emphasis must be placed on the enrollment of women from
high-risk groups (e.g., racial/ethnic minorities, especially Blacks
and Hispanics, drug abusers, partners of drug abusers, etc). A
pregnant woman enrolled in perinatal studies will count as one
enrollee.
Document the capability to enroll a MINIMUM OF 25 NEW PATIENTS INTO
PEDIATRIC PROTOCOLS/YEAR. This minimum number is required in order to
qualify as a prospective clinical trials unit.
Each applicant must describe the
o demographic features of pediatric patients and pregnant women in
the catchment area, including number of AIDS cases, HIV
seroprevalence data, sex, race/ethnicity, and risk transmission
categories. If available, include a categorization of HIV status
(P0, P1, etc.) for pediatric patients currently being seen or
anticipated.
o primary source of study subjects (i.e., inpatient or outpatient
units providing primary care, consultative services, HIV testing
sites, referrals from community-based physicians or agencies, or
other). If utilizing referral sources, the policies and procedures
for communication, outreach, follow-up by research staff or primary
care provider, and transfer of care back to primary care provider
upon completion of study must be provided;
o staff commitment for outreach and recruitment (e.g.,
paraprofessionals [ex-drug users, etc], and outreach workers, social
workers, psychologists/ counselors). Describe the responsibilities
of each. Culturally sensitive individuals representative of the
target population(s) must be included among staff.
o outreach to infants, children, adolescents and pregnant females or
HIV infected mothers. If applicable, letters of agreement with other
institutions should be provided;
o for new applicants, provide past records of clinical trials or
data from inpatient or clinic records showing number of patients
under care (or projected) and an estimation of percentage suitable
for Pediatric ACTG studies.
o ANCILLARY CARE/LINKAGES (5 page limit)
Describe the mechanisms in place to deliver ancillary health care in
order to facilitate participation of pediatric patients in research.
o Describe how ancillary care (e.g., language interpretation, child
care, patient transportation to/from the research center, etc) will
be provided to pediatric patients and their families. Provide
evidence of commitment to the provision of personnel (e.g., social
workers, paraprofessionals, patient advocates, etc) who counsel
patients, especially mothers and adolescents, in dealing with issues
which may impact on their participation in clinical trials.
Culturally sensitive individuals representative of the target
population(s) must be included among staff.
o Linkages - to increase the collaborative provision of health care
and multidisciplinary services at the community level and to
establish interaction between the ACTU, the community, and
community-based organizations, the following support linkages are
either REQUIRED or strongly ENCOURAGED. Letters of agreement in
support of these linkages as well as definitive plans to operate the
linkages must be provided
o Community Advisory Board [REQUIRED]. A Community Advisory Board
(CAB) must be established at each site. The CAB serves as a bridge
between the ACTU and the community. Describe the specific role and
relationship of the CAB to the research and operations of the
applicant institution. Specify the composition of the CAB, including
AIDS-related expertise of participants, functions performed for the
ACTU, and proposed meeting schedule. Inclusion of women and
minorities is required; their participation on the CAB should be
reflective of the demographics of HIV-infected persons in the
catchment area.
o National Institute of Child Health and Human Development (NICHD)
[REQUIRED]. Applications from institutions where there are NICHD
funded sites will be required to include a letter of agreement
between the NICHD unit and the proposed ACTU. Included in the letter
should be: screening/ recruitment procedures for HIV-infected
children; whether facilities are shared; whether both sites are or
will be participating in ACTG protocols, and if so, how assignment to
ACTG protocols is or will be made. Ordinarily, an applicants may not
receive funding simultaneously from more that one NIH institute
(e.g., NIAID and NICHD) to participate in ACTG protocols. [See
Appendix II for a listing of NICHD sites.]
o National Hemophilia Foundation (NHF). [REQUIRED] Applicants who
participate in the NIAID sponsored Hemophilia Contract Program may
respond to this RFA. However, if successful, the applicant may not
receive duplicate support for the same type of work from both
agencies. Applicants wishing to establish an ACTU within the same
institution as an NHF site will be required to
include a letter of agreement from the Principal Investigator of the
NHF site in which the relationship between the two sites is
described. The following items should be included:
screening/recruitment procedures for HIV-infected children; whether
facilities are shared; whether both sites are (or will be)
participating in ACTG protocols, and if so, how assignments to ACTG
protocols are (or will be) made. [See Appendix II for a listing of
NHF sites.]
o General Clinical Research Center (GCRC) [ENCOURAGED]. Applicants
from institutions which have a GCRC funded by the National Center for
Research Resources (NCRR) may wish to identify the GCRC as a resource
for conducting the proposed research. In such a case, a letter of
agreement from either the GCRC Program Director or the Principal
Investigator should be included with the application.
o Health Resources and Service Administration (HRSA) Pediatric AIDS
Demonstration Project [ENCOURAGED]. Applicants are encouraged to
establish linkage with a HRSA funded pediatric project if one is
located within the same region is encouraged and a letter of
agreement and a plan describing the relationship should be included.
[A listing of HRSA Pediatric AIDS Demonstration Projects may be found
in the Appendix IV].
o National Institute on Drug Abuse (NIDA) Treatment and Research
Centers [ENCOURAGED]. In order to increase the number of
HIV-infected drug users in ACTG protocols. Applicants are encouraged
to establish linkages with NIDA Treatment and Research Centers
located in the same community. In the event that there is not a NIDA
center in the catchment area, applicants may establish linkage with
drug treatment centers. [A listing of the NIDA Treatment and
Research Centers may be found in Appendix V].
o Applicants are strongly encouraged to form other linkages,
including but not limited to: community-based organizations that
serve children at increased risk for HIV infection, designated State
AIDS Centers, the NCI lymphoma network, and community-based AIDS
clinics. A letter of agreement for each linkage should be included
with the application.
o DATA MANAGEMENT PLAN (5 page limit)
Describe a plan for managing the clinical trials data from both
inpatient and outpatient studies: i.e., collection, entry,
maintenance, monitoring, storage, and transmission. The manner in
which clinical sites interact with the Statistical and Data Analysis
Center (SDAC) is described in Appendix I, F.1. The scope of data
management activities are reflected in the recommended guidelines for
personnel that are listed in Appendix VI.
o The plan should take into account that Federal Regulations require
the retention of research records for investigational drugs for two
years after a marketing application is approved for the drug. If an
application for the drug is not approved, the records must be
retained for two years following discontinuation of shipment and
delivery of the drug and after FDA has been notified.
o The plan should include the following
o documentation of the expertise and duties of the data manager
regarding PC hardware, software and DOS, and oversight/supervision;
o description of procedures for
o completion of the forms required for patient study visits; (the
estimated time from patient visit to completion of data entry should
be noted)
o transcription of laboratory data from lab slips to data forms in
preparation for data entry;
o data entry into the ACTG PC-based distributed data entry system in
a timely fashion;
o establishment/maintenance of a filing system for patient charts
and completed data forms, and procedures for ensuring the security of
these files;
o description of procedures for educating and training staff on the
above protocol-related issues;
o provision of adequate resources with respect to both staff and PC
hardware and software to accomplish these responsibilities. NOTE: a
list of computer equipment that will be required for a clinical
trials unit is located in Appendix VII. Funds to purchase required
equipment may be requested as part of the application, with adequate
justification;
o a plan for establishing on-site quality assurance procedures to
ensure the accuracy and completeness of all research records and
compliance with Federal Regulation regarding clinical trials (e.g.,
Institutional Review Board approval and informed consent process);
and
o mechanisms for interacting with SDAC.
o PHARMACY PLAN (5 page limit, plus supporting letters)
Applications must provide a pharmacy plan which addresses the
development and maintenance of the investigational drug control
systems for the proposed ACTU, and if applicable, any subunit sites
(see below).
o The pharmacy plan must include the guidelines set out in the ACTG
Pharmacy Manual (available upon request from the ACTG Operations
Office, 301- 230-3150) and FDA regulations involving the use of
investigational drugs. These guidelines include the following:
o technical procedures for control of drug ordering;
o procedures for dispensing drugs;
o procedures for accountability of drug inventory; and
o drug storage requirements.
Letter(s) of agreement in support of the plan(s) from pharmacy
personnel at participating institutions should be included.
o The plan must include provision of adequate pharmacy staff for the
proposed ACTU and complete discussion of duties and responsibilities.
Guidelines for levels of pharmacy staff based on projected accrual
are included on the form, "PEDIATRIC ACTU BASE BUDGET", under
Appendix VI.
o IMMUNOPHENOTYPING, Required (3 page limit, plus supporting
letters)
Applicants must be able to perform the following flow cytometric
immunophenotyping measurements at the proposed ACTU. These
measurements were established by the Immunology Core Committee of the
ACTG.
The laboratory must have the capability to perform two- and
three-color flow cytometric immunophenotyping on whole blood samples
using a laser-based instrument on a minimum annual number of 500
samples. Minimum required immunophenotypes include: CD4, CD8, CD3,
CD19, CD45, and CD14. Other phenotypes (e.g. CD25, CD38, CD45RA,
CD45RO, DR, CD56, CD16, etc.) may be required in the context of ACTG
protocols. (The use of existing ACTG -certified laboratories in the
same community, whenever possible, is strongly encouraged. For
example, an applicant from an institution where there is an adult
ACTU laboratory should use the adult laboratory rather than establish
a new one.) For the analysis of ACTG specimens, awardee laboratories
shall be required to adhere to methodologic guidelines set forth by
the DAIDS Flow Cytometry Advisory Committee and to participate in the
DAIDS immunophenotyping quality assessment program.
The narrative description should contain the following:
o description of the technical and analytic methodologies used in
the laboratory for the enumeration of immunophenotypes
o description of the flow cytometer(s)
o the laboratory's reference range(s) for adult and pediatric
populations
o qualifications and experience of key laboratorypersonnel
o description of internal Quality Control/Quality Assurance (QC/QA)
program
o involvement in external QC/QA and/or proficiency testing programs
o breakdown of costs (e.g., personnel, supplies, etc.), including
costs for shipping and processing specimens if these tests are to be
performed off- site.
PART B - LABORATORY SUPPORT FOR CLINICAL TRIALS
A major goal of the ACTG is to maintain the capability to address all
aspects of clinical drug evaluation. To meet this goal, the ACTG
must acquire a depth of laboratory capability concentrated in
pediatric ACTUs in order to address questions that are unique to the
conduct of HIV clinical trials in children and pregnant women. The
DAIDS intends to fund pediatric ACTUs with resources to support
virology, immunology and pharmacology as required in the context of
ACTG pediatric trials.
The Laboratory Support for Clinical Trials components are:
Virology, REQUIRED
Immunology, OPTIONAL
Pharmacology, OPTIONAL
o VIROLOGY, REQUIRED (10 page limit, plus supporting letters)
Each applicant must submit a plan describing a capability to perform
and/or obtain (via collaboration) virology laboratory services as
required for evaluation of patients enrolled in ACTG pediatric
clinical trials.
Budgets should reflect the costs for performing and/or obtaining
virologic testing for patients to be enrolled at the applicant ACTU.
Applicants are instructed not to duplicate the costs for required
virology testing within the clinical base funding.
Applicants proposing to perform any virologic testing on-site must
include, as part of their plan, detailed descriptions of:
o the laboratory equipment and facilities relating to conduct of
virology;
o all relevant methodologies, such as
o procedures for culturing HIV from clinical samples (PBMC &
plasma);
o procedures for performing HIV p24 antigen determinations;
o procedures for performing antiviral drug resistance
(susceptibility) assays;
o procedures for performing HIV DNA & RNA PCR; and
o intralaboratory QC/QA procedures.
Applicants proposing to have virologic testing performed by off-site
collaborators must include, as part of their plan, detailed
descriptions of all relevant methodologies (as described above). In
addition, for each virologic test, applicants must provide the
name(s) and address(es) of the collaborating investigator(s)
performing the test, as well as appropriate documentation (e.g.
letters of agreement) to substantiate the collaborative arrangement.
The use of existing ACTG-certified laboratories in the same
community, whenever possible, is strongly encouraged.
All applicants must include, as part of their plan, a detailed
description of their proposed procedures for the storage of specimens
and maintenance of specimen inventories.
Applicants and/or collaborators approved to perform virologic testing
in support of ACTG pediatric clinical trials (i.e. on-site and off-
site laboratories) shall be required to:
o use the DataWorks software for data transmission;
o participate in the DAIDS virology QA program;
o adhere to ACTG Virology Committee consensus protocols.
Applicants approved to perform on-site virologic testing may be
required to provide specified virology laboratory services to other
sites on a fee-for-service basis.
o IMMUNOLOGY, Optional (10 page limit, plus supporting letters)
The primary objective of this component is to establish a capability,
within pediatric ACTUs, to evaluate the impact of experimental
immune-based therapies (e.g. active immunization, passive
immunization, ex-vivo expansion of cellular effectors, cytokine
therapy, modulation of cytokines, general immune modulators, and
genetic therapies) on host immune function.
To support the evaluation of immune-based therapeutic strategies,
applicants shall describe their capability to develop and perform
immunologic assays, such as
o HIV-specific cellular immunity (e.g. cytotoxic T cells,
proliferative responses, etc.);
o HIV-specific humoral immunity (e.g. neutralizing antibody, binding
antibody, etc.);
o non-HIV specific antigen responses (e.g. anti-tetanus),
mitogen-induced proliferative responses);
o markers of immune activation (activation antigen expression,
cytokine production, etc.);
o specific immune responses to opportunistic pathogens.
Applicants awarded funding for this component shall be required to:
o adhere to consensus protocols developed by the ACTG Immunology
Committee
o participate in DAIDS-sponsored quality assessment program(s) (QA)
for immunology.
Also, awardees may be required to perform fee-for- service
protocol-mandated immunology testing on samples obtained from
patients at other ACTUs.
Budgets should reflect the costs to perform the protocol-mandated
immunologic assays (a-e above) for patients at the applicant ACTU.
Applicants for this component are instructed not to duplicate these
immunology costs within the clinical base funding.
Applicants not seeking funding for this component shall include the
costs of protocol-mandated immunology testing in the clinical base
funding.
Applicants who seek but are not awarded funds for this component
shall have their clinical base funding adjusted to provide support to
include the costs of protocol-mandated immunology testing.
o PHARMACOLOGY, Optional (10 page limit, plus supporting letters)
ACTU Pharmacology laboratories will perform protocol-mandated
measurement of drug levels in clinical samples. Applicants should
demonstrate a capability to conduct therapeutic drug level monitoring
using a variety of methodologies. New technologies will also be
implemented as pharmacologic detection procedures improve and/or
require evaluation.
Applicants should describe and document
o procedures to conduct pharmacokinetic analyses of agents utilized
in the treatment of HIV infection and the opportunistic infections
associated with AIDS in children;
o capability to perform a minimum number of 500- 1000 drug level
determinations per year for an experimental agent such as a
nucleoside analog;
o capability to develop new pharmacological assays by describing
past experience in developing and evaluating new clinically relevant
techniques;
o intralaboratory QC/QA procedures and participation and performance
in any external QA programs.
Applicants awarded funding for this component shall be required to
o adhere to consensus protocols developed by the ACTG Pharmacology
Committee
o participate in DAIDS-sponsored QA program(s) for pharmacology.
Awardees may be required to perform fee-for- service
protocol-mandated pharmacology testing on samples obtained from
patients at other ACTUs.
Budgets should reflect the costs to perform protocol-mandated
pharmacologic assays for patients at the applicant ACTU. Applicants
seeking funding for this component are instructed not to duplicate
the costs for B.3 pharmacologic testing within the clinical base
funding.
Applicants not seeking funding for this component shall include in
their clinical core budget the source and costs of protocol-mandated
pharmacologic testing.
Applicants who seek but are not awarded funds for this component
shall have their clinical base funding adjusted to provide support to
include the costs of protocol-mandated pharmacologic testing.
PART C - DEVELOPMENTAL RESEARCH
Access to clinical samples from patients with detailed medical
histories provides a unique resource to support developmental
research leading to improved diagnosis, monitoring and treatment of
individuals with HIV infection. The primary objective of the
developmental research funding is to stimulate investigators to
answer clinically relevant questions utilizing pediatric patient
specimens generated under ACTG protocols. Emphasis in these studies
should be on specific scientific inquiries which make the best use of
resources available through ACTG sites and that address the highest
priority questions that arise from the performance of AIDS clinical
trials in children.
Research permitted within the developmental research areas may be
broad in scope but must be of high clinical relevance.
The Developmental Research components are
Developmental Virology, OPTIONAL
Developmental Immunology, OPTIONAL
Developmental Neuropsychological Assessment,
OPTIONAL
o DEVELOPMENTAL VIROLOGY RESEARCH, OPTIONAL (10 page limit)
Developmental Virology Research projects are encouraged in, but are
not limited to, the following areas
o identification and validation of virologic markers (e.g. viral
phenotypes and/or genotypes) correlating with perinatal transmission,
clinical disease progression and/or treatment effects in children;
o quantitative determination of viral burden and infectivity of HIV
virions or cell-associated virus in bodily fluids/tissues and their
correlation with perinatal transmission as well as clinical
parameters of HIV infection in children;
o development of improved methodologies to screen for antiviral drug
resistance and to design and evaluate strategies to counteract drug
resistance in children;
o characterization of mechanisms of resistance, stability and
virulence of drug resistant phenotypes, including development of
propagation procedures for optimal cultivation of drug resistant
isolates from potentially heterogeneous viral populations.
Where applicable, applicants should describe the capability to
develop novel assays for virologic markers, describing past
experience in developing and evaluating new clinically relevant
laboratory techniques.
o DEVELOPMENTAL IMMUNOLOGY RESEARCH, OPTIONAL (10 page limit)
Developmental Immunology Research projects are encouraged in, but are
not limited to, the following areas
o maternal immunologic parameters and their association with risk of
perinatal transmission and disease progression in children;
o immune cell phenotypic/functional characteristics (e.g.
HIV-specific CTLs, HIV- specific humoral responses, HIV or other
antigen- specific proliferation, cytokine production, etc.) and their
relationship to clinical disease progression in children;
o mechanisms of immune activation and/or immune cell depletion and
their relationship to clinical disease progression in children;
o evaluation of the immune response to AIDS- associated
opportunistic pathogens;
o evaluation of the immune response to therapeutic agents.
o DEVELOPMENTAL NEUROPSYCHOLOGICAL ASSESSMENT RESEARCH, OPTIONAL (10
page limit)
Developmental neuropsychological research projects are encouraged in,
but are not limited to, the following areas:
o identification of specific early markers of neurologic or
neuropsychologic deterioration in patients enrolled in ACTG pediatric
protocols;
o development and validation of "mini" neurologic or
neuropsychologic screening exams in relation to more comprehensive
neurologic or neuropsychologic "gold standard" evaluations;
o assessment of the correlation of neuroimaging, or neurologic
laboratory studies with neurologic or neuropsychologic findings;
o assessment of critical sociodemographic confounders which need to
be gathered in ACTG pediatric clinical trials and controlled for in
analyses of study drug effects on neuropsychologic outcomes;
o development of monitoring mechanisms to ensure timeliness and
quality of pediatric neurologic and neuropsychologic data gathered in
ACTG pediatric protocols.
II. ORGANIZATION OF THE APPLICATION
All applications must be submitted on the Form PHS 398 (rev. 9/91).
The application should be assembled and paginated as one complete
document. A separate narrative and itemized budget with
justifications must be prepared for each component for which support
is requested.
GENERAL INSTRUCTIONS FOR PREPARING THE APPLICATION FOR PARTS A, B,
AND C
Page 1 of PHS 398
Complete items 1-18 as instructed. Please note that this should be
page one for the entire application and that all succeeding pages
should be numbered consecutively.
Items 7 & 8: The budget requested should represent the TOTAL budget
of the entire application including Clinical Base Budget (PART A),
Laboratory Support (PART B) and Developmental Research (PART C).
Item 7 should indicate the total costs for the first year of support
(item 7a should tally with the total figure indicated at the bottom
of PHS form page 4) and item 8 should indicate the total costs for
all four years of support (item 8a should tally with the
corresponding figure at the bottom of PHS form page 5.)
Item 9: All performance sites whether receiving support or not
should be listed.
Page 2 of PHS 398
The abstract should contain a brief summary of the proposed work and
objectives for the application.
Under "Key Personnel Engaged on Project" list the Principal
Investigator of the ACTU and the Program Director of each component.
Page 3 of PHS 398
Prepare a detailed Table of Contents that will allow reviewers to
readily locate specific information for each component.
Pages 4 and 5 of PHS 398
INDIVIDUAL BUDGET PAGES FOR EACH COMPONENT: a detailed 12-month
budget with justifications (use page 4 of PHS Form 398) with an
corresponding four-year summary budget page (use PHS Form page 5)
must be prepared for EACH component applied for and for which support
is requested.
If there is an unusual item requested in one of the future years
which had not been requested in the first year, e.g., an item of
equipment requested in the second or third year, this item must have
a detailed justification.
FOR MORE DETAILED INSTRUCTIONS ON THE BUDGET SEE ITEM III, "BUDGET
REQUIREMENTS", BELOW.
Pages 6 and 7 of PHS 398
Prepare biographical sketches and information on Other Support for
all professional personnel participating in the pediatric ACTU for
whom support is requested. The biographical sketches and information
on other support should be placed at the end of the application, with
the Principal Investigator first, followed by other key professional
personnel in alphabetical order, appropriately numbered and
referenced in the Table of Contents.
III. BUDGET REQUIREMENTS
All applicants for pediatric ACTUs must apply for the Pediatric
Clinical Trials Unit (PART A) and Laboratory Support for Virology
(PART B.1).
Laboratory Support for Immunology (PART B.2), Pharmacology (PART B.3)
and the Developmental Research Components (PART C) are OPTIONAL. An
award for any laboratory component is contingent on receiving an
award for Part A.
Laboratory Support/Developmental Research (PARTS B AND C)
Applicants applying for PARTS B and C, who are employed by
institutions that have adult ACTU laboratories could use the adult
unit to perform the laboratory work in PARTS B and C. The funds for
laboratory support will be awarded to and administered by the
Pediatric ACTU.
Applicants for Developmental Research in Virology (C.1) and
Immunology (C.2) must apply for and receive an award for virology and
immunology (PART B.1 and B.2) respectively to be eligible for
Developmental Research awards (PART C) in these disciplines.
COMPOSITE FIRST YEAR BUDGET: Using page 4 of the application prepare
a composite budget for the first 12 month budget period. The
Composite Budget should include the subtotals from the individual
detailed budgets for the first 12-month budget period for each
component part in the application: Part A, Part B1, as well as any
(optional) component portion of Part B or C for which funds are being
requested. Justification for budget elements should be presented in
each individual component budget rather than with the Composite
Budget.
NOTE: FOR EACH INDIVIDUAL FIRST YEAR BUDGET PAGE (I) PREPARED FOR A
GIVEN COMPONENT, A CORRESPONDING FOUR-YEAR SUMMARY BUDGET (II) SHOULD
ALSO BE PREPARED. PAGE 4 OF PHS FORM 398 SHOULD BE USED FOR ALL "A"
BUDGETS. PAGE 5 OF PHS FORM 398 SHOULD BE USED FOR ALL "B" BUDGETS.
FOR EXAMPLE:
o (I) 12 MONTH BUDGET FOR PART A
o (II) FOUR YEAR SUMMARY BUDGET FOR PART A
o (I) 12 MONTH BUDGET FOR PART B1
o (II) FOUR YEAR SUMMARY BUDGET FOR PART B1
o (I) 12 MONTH BUDGET FOR EACH COMPONENT OF PART B BESIDES B1 FOR
WHICH SUPPORT IS BEING REQUESTED
o (II) FOUR YEAR SUMMARY BUDGET FOR EACH COMPONENT OF PART B
BESIDES B1 FOR WHICH SUPPORT IS BEING REQUESTED
o (I) 12 MONTH BUDGET FOR EACH COMPONENT OF PART C FOR WHICH
SUPPORT IS BEING REQUESTED
o (II) FOUR YEAR SUMMARY BUDGET FOR EACH COMPONENT OF PART C FOR
WHICH SUPPORT IS BEING REQUESTED
o (I) COMPOSITE 12 MONTH BUDGET: TOTAL OF ALL (I)S ABOVE
o (II) TOTAL SUMMARY FOUR YEAR BUDGET: TOTAL OF ALL (II)S ABOVE
ALL BUDGET PAGES MUST BE PLACED FOLLOWING PAGE 3 OF THE OVERALL
APPLICATION, WITH THE OVERALL BUDGETS BEING FIRST, FOLLOWED BY THE
BUDGETS FOR PART A, THEN B1, AND SO ON. THESE BUDGET PAGES SHOULD BE
NUMBERED CONSECUTIVELY AND BE APPROPRIATELY REFERENCED IN THE "TABLE
OF CONTENTS." EACH BUDGET PAGE MUST HAVE THE APPROPRIATE TITLE
CORRESPONDING WITH THE TITLE OF THE PROJECT OR COMPONENT, IN THE
UPPER MARGIN OF THE PAGE.
A SUMMARY TOTAL BUDGET: (personnel, equipment, supplies etc) for all
four years of requested support should be presented using page 5.
The total budget for all future years of requested support is a
composite of the individual FOUR-YEAR budgets of each component.
Justification for the budget elements should be presented in the
individual components.
PREPARATION OF BUDGETS FOR PARTS A, B, AND C
PART A: CLINICAL BASE BUDGET
That portion of the ACTU budget specifically related to patient care
is called Clinical Base Budget. It will include the resources
required to accrue a projected number of new patients on an annual
basis.
Clinical Base Budget should include
Protocol Specific Costs: All resources necessary for the study of a
projected number of patients on ACTG protocols for the duration of
the protocol. This may be multi-year funding if the duration of the
study is greater than one year.
Costs Not Directly Related to a Specific Protocol: ancillary services
and outreach efforts necessary for the recruitment and retention of
patients; screening costs for the identification of eligible study
participants; costs associated with performing flow cytometry (CD4,
CD8, etc); and administrative costs.
Clinical budgets will be constructed by relating the cost of
performing a protocol to the projected number of patients to be
accrued. These costs will represent the major portion of the
clinical base budget.
CONSTRUCTION OF THE CLINICAL BASE BUDGET FOR PART A (PHS Form 398
Page 4):
Guidelines for developing base budgets for pediatric units may be
found in under Appendix VII, "Pediatric ACTU Base Budget". Base
budgets will provide support for the supplies, equipment, patient
care cost and ancillary services, and personnel necessary for
conducting pediatric clinical trials.
Personnel - Support for specialized personnel essential to studies in
neurological assessment and for obstetrical and perinatal services
should be included in the base budget. In the ACTG, statistical
support is provided by SDAC and thus statisticians will not be
supported under this RFA.
Patient Care - Include the projected costs for performing clinical
laboratory tests and charges for in- patient care that will be
required by clinical trials protocols. The amount requested should
be justified based on the number of patients the ACTU projects to
accrue annually.
Additional information: Appendix VIII contains a list of patient
care laboratory procedures which has been itemized to reflect the
clinical laboratory tests necessary for conducting the study.
Applicants are required to provide the costs for performing these
tests at their institution. If multiple clinical performance sites
are proposed in the application which have significantly different
costs, the applicant may provide individual laboratory costings for
each site. These costs should be attached as an APPENDIX to the
application. This information will be used by the Initial Review
Group to evaluate the reasonableness of patient care costs being
requested.
Equipment - Computer equipment and accessories may be requested if
justified. See Appendix VI for required equipment.
Supplies - Clinical, administrative, pharmacy, and those supplies
necessary for performing flow cytometry should be included.
Travel - Limited to a total of 24 trips annually to ACTG meetings.
Travel funds for personnel listed in Parts B and C should be
requested in those component budgets. Scientific meetings are
limited to $2000/year and foreign travel, if applicable, to
$3000/year.
INCUMBENT APPLICANTS
Renewal applications from incumbents should include a SEPARATE
detailed budget to cover the protocol specific costs of continuing
patients that are projected to be on study as of 9/93. This budget
should be entitled, "Component A - Continuing Patients" and should
include all costs required for the currently enrolled patients to
complete the protocol. At the time an award is made this request may
be negotiated to adjust for the actual number of patients on study.
PART B- LABORATORY SUPPORT BUDGET
Using the format in the Form PHS 398, a detailed budget for the first
year and for all four years of support must be prepared for each
laboratory component for which you are applying. It is nticipated
that Laboratory Support awards (Part B) will not exceed $ 200,000
direct costs per year per laboratory.
PART C- DEVELOPMENTAL RESEARCH BUDGET
As with Part B above, a detailed 12-month budget and a summary
four-year budget must be prepared for each developmental research
project proposed, following the instructions in Form PHS 398. It is
anticipated and that developmental research awards (Part C) will not
exceed $100,000 direct costs annually per component. Applicants may
apply for more than one optional component.
Each project under Laboratory Support and Developmental Research
components will be REVIEWED INDEPENDENTLY and should contain
sufficient information and detail to assure a thorough review.
SPECIAL INSTRUCTIONS: PART B.1
SAMPLE OPTIONS for Laboratory Support for Virology (B.1)
o Perform all protocol-mandated virological tests on site (HIV p24,
HIV culture (PBMC, plasma), antiviral drug resistance assay, PCR,
etc.).
o Perform protocol-mandated HIV p24 antigen assays and HIV PBMC
cultures on site and collaborate with another (off-site) ACTG
virology laboratory to obtain the remaining tests on a fee-
for-service basis.
o Arrange for all protocol-mandated virologic assays to be performed
by another ACTG virology laboratory (off-site) on a fee-for-service
basis.
Construction of a Detailed Budget for PART B.1
The budget justification for Part B.1 must contain the estimated
number of samples to be evaluated annually (based only on samples
from patients enrolled at the applicant ACTU) for each test and the
total estimated cost/test.
Sample budget justifications referring to possible options A, B, and
C above
o All necessary personnel, equipment, supplies, etc. should be
included.
o All necessary personnel, equipment, supplies etc. should be
included for the HIV p24 antigen assays and HIV PBMC cultures. The
costs of processing (personnel and supplies) and shipping the
remaining samples to other laboratories should also be included. The
total costs for those tests that will be performed on a
fee-for-service basis should be included in the Other Expenses
category of the budget.
o The costs of processing (personnel and supplies) and shipping the
samples should be included. The total costs for all tests to be
performed on a fee-for-service basis should be included in the Other
Expenses category of the budget.
SPECIAL INSTRUCTIONS: PART B.2, B.3, AND PART C
Follow the instructions in PHS 398 starting with the preparation of
the Detailed Budget. If information (facilities available,
procedures for handling and disposing of HIV infected material etc.)
has been presented in a prior component of the application, it may be
cross referenced in a subsequent component.
LETTER OF INTENT
Prospective applicants are asked to submit by November 13, a letter
of intent (maximum of three pages) that includes a descriptive title
of the overall proposed research, the components that will be
included, the name and institution of the Principal Investigator and
a brief description of the research proposed for each component in
which participation is planned. Names of prospective
co-investigators and other key personnel should be included. The
letter of intent is requested in order to provide an indication of
the number and scope of applications to be reviewed and to promote
early interactions between applicants and NIAID staff. The letter of
intent does not commit the sender to submit an application, nor is it
a requirement for submission of an application. The letter of intent
should be sent to Ms. Tina Johnson, M.A. (SEE INQUIRIES BELOW)
APPLICATION PROCEDURES
Pre-application Meeting - In order to provide a forum during which
prospective applicants may obtain additional information, further
clarification and assistance, a Preapplication Meeting will be held
on December 7, 1992 in Bethesda, MD. The meeting date and location
will also be announced in the NIH Guide for Grants and Contracts. In
addition, Ms. Johnson may be called at (301) 496-8214 after November
6, 1992 to obtain specific information about the meeting.
Application Preparation and Submission - The research grant
application form PHS-398 (rev 9/91) must be used in applying. These
forms are available at most institutional business offices or from:
Office of Grants Inquiries, Division of Research Grants, National
Institutes of Health, Westwood Building, Room 449, Bethesda, MD
20892, (301) 496- 7441.
It is important to follow the instructions for preparing the
application as described in both the PHS 398 form and in this RFA.
Failure to do so will result in an application with insufficient
information for appropriate scientific review.
For purposes of identification and processing, the RFA number, RFA
92-AI-10, and title,"PEDIATRIC AIDS CLINICAL TRIALS UNITS", should be
typed on line 2 of the face page of the application form and the
"YES" box should be marked. Designate the PHS component as
NIAID/DAIDS/TROP.
The RFA label available in the 9/91 revision of the PHS-398
application form should be affixed to the bottom of the face page of
the application. Failure to use this label could result in delayed
processing of the application such that it may not reach the review
committee in time for the review.
Submit a signed, typewritten original of the application, and three
(3) exact, single-sided photocopies (including the Appendices), in
one package to
DIVISION OF RESEARCH GRANTS
Westwood Building, Room 240
National Institute of Health
Bethesda, MD 20892
AT THE TIME OF SUBMISSION, TWO (2) ADDITIONAL COPIES OF THE
APPLICATION INCLUDING APPENDICES, EACH CLEARLY MARKED REGARDING THE
COMPONENT OF THE APPLICATION TO WHICH THE APPENDIX PERTAINS, MUST
ALSO BE SENT DIRECTLY TO
Dianne Tingley, Ph.D.
Chief, AIDS Research Review Section
Scientific Review Branch, NIAID
National Institutes of Health
Solar Building, Room 4C16
6003 Executive Boulevard
Bethesda, MD 20892
Applicants who wish to use express mail or courier service should
substitute Rockville, MD 20852 for the city, state, zip.
The deadline for receipt of applications is January 6, 1993.
Applications received after this date will be considered as
nonresponsive to this RFA and returned without review.
REVIEW CONSIDERATIONS
Upon receipt, applications will be reviewed by the DRG staff for
completeness and by the NIAID staff for responsiveness. Incomplete
applications and those judged to be unresponsive to the RFA will be
returned to the applicant without further consideration. Examples
that will result in the application being considered nonresponsive
include, but are not limited to: 1) failure to address all required
items of the Pediatric ACTU component and 2) submission of optional
components that are not presented as separate narratives with
separate budgets.
Those applications that are complete and responsive to triage by a
Special Review Committee (SRC) to determine their scientific merit
relative to other applications received in response to this RFA. The
NIH will administratively withdraw from competition those
applications judged to be noncompetitive and notify the applicants
and the institutional business officials. Those applications judged
to be competitive will undergo further evaluation for scientific
merit by a Special Review Committee consisting primarily of
non-Federal scientific experts. To the extent possible, members of
the committee that conducted the triage will also serve on this
committee. The second level review will be provided by the National
Advisory Allergy and Infectious Diseases Council.
LABORATORY SUPPORT AND DEVELOPMENTAL RESEARCH
Applications for Laboratory Support and Developmental Research will
undergo the same dual review process and considerations as
applications for Part A. These applications will be evaluated
independently from the evaluation of Part A.
REVIEW CRITERIA
The following factors will be considered in the scientific and
technical review of Pediatric AIDS Clinical Trials Review, PART A:
o Past clinical trials experience in conducting research on
perinatal transmission of HIV, antiretroviral therapy, and treatment
of OIs including the ability to recruit and retain study
participants, especially members of underrepresented group;
o Adequacy of scientific understanding of the problem as evidenced
by the plan for proposed studies of interruption of perinatal
transmission of HIV (e.g., phase I,II,III, combination therapy, and
immune-based therapy); antiretroviral therapy (e.g., phase II/III);
and treatment and prophylaxis of OIs (e.g., phase I,
pharmacokinetics);
o The qualifications and expertise of the Principal Investigator and
key personnel in the area of perinatal transmission, antiretrovirals,
and OIs as required by this RFA, and their past experience in
conducting clinical trials;
o Quality of a plan for the transfer of mothers from maternal/infant
protocols into adult protocols;
o Adequacy of the organizational structure, including the
relationship between the pediatric clinical trials unit and the
parent institution and other consortium arrangements, necessary to
support pediatric clinical studies of antiretrovirals, OIs, and
prevention of perinatal transmission;
o Adequacy of the physical facilities available for performing both
outpatient and inpatient pediatric and perinatal studies;
o Strength of the administrative experience of the Principal
Investigator and key staff, including past experience, in conducting
all types and phases of clinical trials;
o Inclusion among staff of culturally sensitive individuals
representative of, or experienced and sensitive to the needs of, the
targeted population(s);
o Strength of the outreach/recruitment plan for enrollment of
pediatric patients, adolescents, and pregnant women. Special
emphasis should be placed on women who are minority members, or abuse
drugs, or are partners of drug abusers;
o Quality of the plan for provision of ancillary care (including
commitment to provision of staff and linkages with state and federal
agencies) to increase accrual of HIV-infected pediatric, adolescent,
and pregnant female patients;
o Adequacy of the data management plan;
o Quality of the pharmacy plan; and
o Laboratory capability with respect to immunophenotyping for
standard of care tests.
For optional studies on adolescents and neuropsychological and
neurologic testing
o Quality of the plan for studies of adolescents;
o Quality of the plan describing past experience in studies of
neuropsychological testing;
o Adequacy of scientific understanding of the problem as evidenced
by the plan for proposed studies for neuropsychological assessment
research;
o The qualifications and expertise of the designated investigator(s)
and key personnel in the area of neuropsychological assessment as
emphasized by the program and their past experience in conducting
this type of research;
Laboratory Support for Clinical Trials (PART B)
The following factors will be considered in the scientific and
technical review of the applications for Virology, Immunology, and
Pharmacology Laboratory Support components:
o Evidence of appreciation of the depth and scope of scientific
issues involved;
o Prior participation or experience in relevant quality control
programs;
o Adequacy of the proposed procedures for receipt, storage and
handling of samples from other sites, and for timely reporting of
data;
o Qualifications, expertise, experience and time commitment of the
Principal Investigator and key personnel; and
o Adequacy of the available resources and facilities.
Developmental Research (PART C)
The following factors will be considered in the scientific and
technical review of the applications for Developmental Virology,
Developmental Immunology and Developmental Neuropsychological
Assessment research
o Originality and uniqueness of proposed research;
o Relevance of the proposed research to the clinical objectives of
the ACTG;
o Availability of required clinical samples (where applicable;
o Qualifications, expertise, experience and time; commitment of the
Principal Investigator and key personnel; and
o Adequacy of the available resources.
CONDITIONS FOR AWARD
Although the predominant criteria for funding priorities will be the
scientific merit and technical proficiency of Part A of the
application (Parts B and C will be evaluated independently however,
award considerations will be contingent upon receipt of a Part A
award, see page 33) as judged by peer review, after the applications
have been approved by the NIAID Advisory Council, staff reserves the
right to give consideration to the following factors in the final
selection of applications to be funded: (1) inclusion of populations
currently underrepresented in clinical trials; (2) HIV
prevalence/geographic distribution; (3) cost effectiveness of
conducting clinical trials; (4) the overall capacity of funded
institutions to carry out the research objectives of the group (see
Research Objectives, page 5); and (5) the quality of past
performance.
INQUIRIES
Written or telephone inquiries concerning this RFA are encouraged.
The following NIAID staff will be available to answer questions
regarding the preparation of the application in response to this RFA.
Direct inquiries concerning the programmatic aspects of this RFA to
Tina Johnson, M.A.
CRMB/DAIDS
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2A09
6003 Executive Boulevard
Bethesda, MD 20892
Telephone: (301) 496-8214
Direct inquiries regarding review aspects and requirements in the
application to
Dianne Tingley, Ph.D.
Scientific Review Branch
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C16
6003 Executive Boulevard
Bethesda, MD 20892
Telephone: (301) 496-8214
Direct inquiries pertaining to budget issues to
Ms. Mary Kirker
Deputy Chief, Grants Management Branch
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B22
6003 Executive Boulevard
Bethesda, MD 20892
Telephone: (301) 496-7075
For express mail or courier service, please send to: Rockville, MD
20852
SCHEDULE
Letter of intent receipt date: November 13, 1992
Pre-application meeting date: December 7, 1992
Application Receipt Date: January 21, 1993
Special Review Committee: March 1993
NIAID Advisory Council Review: June 1993
Anticipated Award Date: September 1, 1993
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic
Assistance, 93.856 - Microbiology and Infectious Diseases Research
and 93.855 - Allergy, Immunology and Transplantation Research. Awards
are under authorization of the Public Health Service Act, Title IV,
Part A, Public Law 78-410 as amended, and administered under PHS
grant policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.
This program is not subject to the intergovernmental review
requirements of Executive Order 12371 or Health Systems Agency
Review.
.
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